Important Lessons from ONTARGET

ACE inhibitor and ARB had similar effects on cardiovascular outcomes in high-risk patients.

In the past year, an important landmark study demonstrated therapeutic equivalence of the ACE inhibitor ramipril and the angiotensin receptor blocker (ARB) telmisartan in reducing the risk of all forms of atherosclerotic events.

Until publication of The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), there was no evidence in a head-to-head clinical study comparing the efficacy of an ACE inhibitor and an ARB on vascular outcomes in patients who are at high risk for cardiovascular events.

The net results of this trial showed that the two drugs were associated with a similar composite outcome, although the ARB was associated with far fewer adverse effects.

The clinical trial design was straightforward: 25,000 patients with cardiovascular disease (CVD) (85%), hypertension (69%), and/or diabetes (38%) were enrolled in a study to examine the impact on vascular events of ramipril 10 mg/day, telmisartan 80 mg/day, or both drugs, plus additional medication to control BP, cholesterol, glucose, and so forth.

The primary objective of the study was to compare the ACE inhibitor, the ARB, or both on their ability to prevent vascular events in high-risk cardiovascular patients without evidence of heart failure. The primary composite end point was death from cardiovascular causes, including MI, death from stroke, or hospitalization for heart failure.

Secondary end points included the risk for incident heart failure, diabetes, atrial fibrillation, dementia or cognitive function decline, nephropathy, revascularization, death from any cause, angina, transient ischemic attacks, development of left ventricular hypertrophy, microvascular complications of diabetes, BP changes, changes in the ankle-to-arm ratio of BP, and cancer. Patients were followed until a primary event occurred or until the study ended (mean duration 56 months). They were assessed clinically every six months.

In an era in which we now recognize the therapeutic advantage of renin-angiotensin system (RAS) blockade as part of a successful effort to control BP in high-risk patients, demonstration of a clinically equivalent alternative with better tolerability than the traditional ACE inhibitor will increase treatment options for patients. RAS blockers as a group are among the best-tolerated medications for BP control. In some patients, treatment with ACE inhibitors results in discontinuation of therapy due to the presence of a cough or angioedema.

One interesting ONTARGET observation was that the risk of acute renal impairment was significantly higher in the combination group compared with the use of the ACE inhibitor or ARB alone. Dialysis rates were also slightly increased in the combination group vs. ramipril alone.

However, it is important to note that only 113 total events were reported in more than 25,000 patients enrolled in the study. One may question why dual RAS predisposed patients to an increased risk for acute renal dysfunction.

Although there are no clear explanations, it is possible that using both RAS blockers together made patients more susceptible to reductions in volume (e.g., GI syndromes, etc.). Overall, patients tolerated the monotherapies similarly, with 88.6 % of the telmisartan patients and 81.7% of the ramipril patients continuing to take the full dose of the medication at two-year follow-up evaluations.

The total number of discontinuations was significantly lower in the telmisartan group, and telmisartan was associated with significantly fewer episodes of cough and angioedema compared with ramipril. However, the telmisartan group experienced more episodes of hypotension than the ramipril group.

Thus, ONTARGET is an important addition to the literature on the advantage of RAS blockade in patients at high risk for cardiovascular events. The data presented are important, as they extend evidence linking the therapeutic equivalence of an ACE inhibitor and an ARB, as reported in Valsartan in Acute Myocardial Infarction (VALIANT), a study of post-MI patients, and in Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM), a study of patients with systolic heart failure.